Hyaluronan is part of a group of polysaccharides known as glycosaminoglycans. In particular, hyaluronan is a mucopolysaccharide that occurs naturally in the bodies of humans and other animals. The term hyaluronan encompasses hyaluronic acid as well as salts of hyaluronic acid, such as sodium hyaluronate. The term hyaluronate refers to the conjugate base of hyaluronic acid. Hyaluronan is the polyanionic form of hyaluronic acid, which exists in vivo.
In general, glycosaminoglycans are made up of repeating disaccharide units containing a derivative of an aminosugar. The repeating disaccharide unit of hyaluronan consists of alternating glucuronic acid and N-acetylglucosamine units, which are repeated over and over to form long chains. Each repeating disaccharide unit has one carboxylate group, four hydroxyl groups, and an acetamido group. Hyaluronan differs from the other major glycosaminoglycans in that it does not have sulfate groups. The chemical structure of hyaluronan is as follows:

Hyaluronan in the extracellular matrix of various body tissues. In normal physiological states hyaluronan molecules form random coils in the nature of helical ribbons that are stiffened by hydrogen bonds and solvent interactions. The axial hydrogen atoms are relatively non-polar while the equatorial side chains are relatively polar, thereby creating the twisting ribbon structure.
Hyaluronan is synthesized in the body by many types of cells and tends to collect in extracellular spaces where acts as a scaffold for aggrecan self-assembly, thereby combining with other constituents to form supportive or protective networks around the cells. Hyaluronan is present in many body fluids and tissues and is found in relatively high concentrations in vitreous humor and synovial fluid.
Hyaluronan is highly lubricious, hydrophilic and exhibits unique rheological properties. The unique rheology of hyaluronan is believed to be due at least in part to the fact that the hyaluronan polymer coils become entangled with each other at low concentrations and exhibit shear-dependent viscosity at high concentrations. For example, a 1% solution of hyaluronan may exist as a gelatinous mass under ambient conditions but, when compressed, will become less viscous and easily flowable such that it may be injected through a hypodermic needle. Because of this unique rheological behavior, hyaluronan has been referred to as a “pseudo-plastic” material. The hydrophilic nature of hyaluronan is believed to be a function of the fact that hyaluronan forms stiffened helical ribbons as described above. Each such helical ribbon is configured such that it may trap substantial amounts of water (e.g., approximately 1000 times its weight in water).
Hyaluronan has a wide variety of medical and non-medical applications. For example, hyaluronan solutions make excellent lubricants and may allow tissue surfaces to slide over one another. Thus, hyaluronan preparations are sometimes applied to tissues to promote healing and/or to reduce the potential for postoperative adhesion formation. One of its important biological roles is to provide beneficial effects on wound healing in the skin and eyes.
Recently, hyaluronan has been found to enhance corneal epithelial healing and corneal reepithelialization for non-infectious corneal erosion. These beneficial effects can be extended to the management of dry eye syndrome, allergic conjunctivitis, and contact lens wear.
For example, dry eye is a syndrome in which inadequate tear production and inappropriate tear composition causes the cornea and conjunctiva improper wetting. Untreated dry eye can be further deteriorated to produce more severe epithelial erosion, strands of epithelial cells, dry spots on the cornea. These can be complicated further by microbial infection. Thus, an early medical management for the dry eye syndrome would be highly desirable. Such an early treatment of the dryness and irritation of the eye by the use of hyaluronan could be very effective and beneficial medical management of the dry eye.
Additionally, it has been known for a long time that contact lenses which have adsorption of cellular debris, mucus materials, lipids and proteins from the eye can cause irritation and/or infection of the eye. Thus, a biocompatible lubricant, particularly hyaluronan can provide beneficial effects to prevent the deposit from forming in its early stage of deposit formation on the contact lenses in the eye.
As indicated above, beneficial effects of hyaluronan for the health of the eye are great; however, use of hyaluronan has been rather limited due to its chemical instability losing its viscosity and lubricity in aqueous solution.
The prior art has included a number of stabilized hyaluronic acid gels useable for cosmetic tissue bulking. For example, RESTALYNE® Injectable Gel; (Medicis Pharmaceutical Corporation, Scottsdale, Ariz.) is a sterile gel of stabilized sodium hyaluronate. Also, PERLANE® injectable gel (Medicis Pharmaceutical Corporation, Scottsdale, Ariz.) is a sterile gel of hyaluronic acid chemically cross-linked with BDDE, stabilized and suspended in phosphate buffered saline at pH=7 and concentration of 20 mg/mL.
Additionally, the prior art has included a number of hyaluronic acid containing viscoelastic preparations used in cataract surgery. For example, VISCOAT® viscoelastic solution (Alcon) contains purified medium molecular weight sodium chondroitin sulfate and sodium hyaluronate formulated to a viscosity of 40,000±20,000 cps at shear rate of 2 sec−1, 25° C. VISCOAT® viscoelastic solution is relatively unstable at room temperature and its manufacturer recommends that it be stored at 2°-8° C. (36°-46° F.) and warmed to room temperature just prior to use. Also, the ProVisc® viscoelastic solution is a cohesive viscoelastic containing a high molecular weight, non-inflammatory highly purified fraction of sodium hyaluronate, dissolved in physiological sodium chloride phosphate buffer. It is also relatively unstable at room temperature and its manufacturer recommends that it be stored at 2′-8° C. (36°-46° F.) and warmed to room temperature just prior to use. The VISCOAT® viscoelastic solution and the ProVisc® viscoelastic solution are sometimes used and formulated in combination. For example, the DisCoVisc® Ophthalmic Viscosurgical Device (Alcon) is product which combines the VISCOAT® viscoelastic solution and the ProVisc® viscoelastic solution in a single pre-filled syringe and the DuoVisc® Viscoelastic system (Alcon) is a product that provides VISCOAT® viscoelastic solution and the ProVisc® viscoelastic solution in separate pre-filled syringes. Like their individual components, the DisCoVisc® and DuoVisa® products must also be stored at 2°-8° C. (36°-46° F.) and warmed to room temperature just prior to use.
There remains a need in the art for the development of new stabilized glycosaminoglycan materials, such as hyaluronic acid or salts of hyaluronic acid, that are stable when stored at room temperature and which exhibit desirable rheological properties.